Is FMO3 p.Val110Ala (c.329T>C) pathogenic?

FMO3 p.Val110Ala (c.329T>C) is classified Conflicting classifications of pathogenicity in FMO3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.6371); Ultra-rare (popmax 0.03%, amr); Associated with trimethylaminuria.

What condition is associated with FMO3 p.Val110Ala (c.329T>C)?

FMO3 p.Val110Ala (c.329T>C) is associated with trimethylaminuria (ClinVar).

How common is FMO3 p.Val110Ala (c.329T>C) in the general population?

FMO3 p.Val110Ala (c.329T>C) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about FMO3 p.Val110Ala (c.329T>C)?

AlphaMissense predicts likely pathogenic (score 0.6371) — an in-silico prediction, not a clinical call.

FMO3 p.Val110Ala

c.329T>C · rs376881697 · VCV875848

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6371 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trimethylaminuria

Computational evidence

Protein change
AlphaMissense	0.6371	likely pathogenic
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -11.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 25 kb · p 0.27 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/59,954 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.0152% 245/1,612,388 alleles · ultra-rare exomes 218/1,460,164 · genomes 27/152,224 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.45%	222
Remaining individualsnot grpmax-eligible	0.0737%	1,357
Admixed Americangrpmax	0.03%	3,331
Middle Eastern	0.0165%	6,076
African / African-American	0.00401%	24,959
European (non-Finnish)	0.00373%	26,788

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FMO3
Protein: p.Val110Ala
Coding: c.329T>C
MANE Select: NM_001002294
dbSNP: rs376881697
Type: single nucleotide variant
Location: chr1:171107682 (GRCh38)
Gene constraint: LOEUF 1.314 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50

Full FMO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

trimethylaminuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FMO3 c.484+2T>G Likely pathogenic ★★ same condition
FMO3 c.828-2A>G Likely pathogenic ★★ same condition
FMO3 p.Arg223Gln Likely pathogenic ★★ same condition
FMO3 p.Arg223Trp Likely pathogenic ★★ same condition
FMO3 p.Arg238Gln Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Arg238Ter Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Arg492Trp Pathogenic/Likely pathogenic ★★ same condition
FMO3 p.Arg500Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fmo3-p-val110ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown